New Approaches to Catalyst Screening and Development

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This research project builds on a platform being developed by the University of Nebraska research team to exploit enzymes as catalytic reporters to facilitate reaction discovery and catalyst optimization. This approach is termed In Situ Enzymatic Screening. The method utilizes ‘reporting enzymes’ to provide real-time information on the relative rates for a set of parallel organic/organometallic reactions of interest. Parallel screening methods are of interest to chemists in academia and industry as they enable the identification of fundamentally new transformations of novel catalysts for targeted reactions. There is a particular need for focused screening in process chemistry groups in the pharmaceutical industry, where reaction optimization is critical. This project seeks to develop new enzymatic screening tools that are applicable across a range of temperatures and that take advantage of phosphate ester functionality for which enzymatic screens are not yet available. The project will also help build the future STEM (science, technology, engineering, and mathematics) workforce by training a diverse group of undergraduate and graduate students in an interdisciplinary research environment at the chemistry/biology interface, including elements of organic, organometallic, analytical, and enzymatic chemistry. This project will further explore and develop an information-rich parallel screening method, termed In Situ Enzymatic Screening (ISES), that uses enzymes as biomacromolecular sensors to provide read-out directly to the experimentalist. This research builds upon the team's earlier proof-of-concept studies that led to the first examples of catalytic asymmetric allylic amination chemistry with nickel, an earth-abundant metal, and that uncovered a useful new transformation for diversity-oriented synthesis known as thiocyanopalladation/carbocyclization. This proposal seeks to fully launch the ‘phosphate-ISES’ and ‘thermal-ISES’ screening platforms. The former goal is motivated by the emergence and importance of substrates bearing dialkyl phosphate functionalities, an important functional group both for transition metal coordination and for specific chemistry. These new enzymatic screening platforms have been built by expressing and testing candidates for screening enzymes that recognize dialkyl phosphates and/or that operate at elevated temperatures. Preliminary results point to enzymes that produce a UV/vis signal under such conditions, enabling the screening of candidate metal-ligand combinations at elevated temperatures or in reactions where dialkyl phosphate functionalities are critical. These methods are being developed with specific targeted chemistry in mind, particularly the catalytic asymmetric synthesis of alpha-halovinyl amino acids as potential mechanism-based inhibitors for PLP (pyridoxal phosphate) enzymes. This synthetic goal builds on recent developments in this laboratory in which quaternary, alpha-(1’-fluoro) vinyl amino acids were synthesized for the first time. The scientific broader impacts of this work include opening new avenues for the catalyst discovery process and for green and sustainable chemistry.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.